This U54 application submitted in response to RFA CA10-021 Tumor Microenvironment (TMEN) is from the University of Nebraska Medical Center. The overall goal of this application is to define the role of interactions between pancreatic tumor cells and the tumor microenvironment during the development and progression of pancreatic cancer. A hallmark of pancreatic cancer is an extreme fibrotic response, and it is our collective hypothesis that fibrosis promotes signaling to the tumor cells, which promotes tumor growth, invasion and metastasis. Specifically, we will investigate interactions, regulation and contributio of secreted and cell surface molecules expressed by stromal cells, premalignant epithelial cells, and malignant cells. This project brings together investigators with experience in the biology of pancreatic cancer. The Pancreatic Tumor Microenvironment Network (TMEN) will include 4 research projects and 3 shared resources. Project 1: Interplay of tumor microenvironment and MUC4 in pancreatic cancer. Surinder K. Batra, Ph. D. Project 2: Lymphangiogeneis and metastasis during pancreatic cancer. Michael A. Hollingsworth, Ph. D Project 3: Role of N-cadherin in pancreatic tumor microenvironment. Keith Johnson, Ph.D. Project 4: CXCR2-dependent pancreatic cancer progression and metastasis. Rakesh K. Singh. Shared resource 1: Administrative Core; Shared resource 2: Rapid Autopsy Program (RAP) Core Shared resource 3: Genetically engineered Model (GEM) Core, Kay Wagner, Ph.D. The four research projects will investigate the role of microenvironment in the early stages of tumor development (Project 1), tumor progression (Projects 3 and 4) and angiogenesis and metastasis (Project 2). Together the group of investigators will exploit the powerful resources comprising of clinical samples, in vitro cell models and genetically engineered animal models of spontaneous tumorigenesis that exist at UNMC, to unravel the complex interplay between the components of tumor microenvironment and tumor cells in pancreatic cancer initiation and progression. With the expertise of the involved investigators in TME, we seek to improve our understanding of the underappreciated role of tumor microenvironment in pancreatic cancer and establish potential therapeutic relevance.